Method for the preparation of aminophthalidylalkane salts



Patented Jan. 8, 1952 METHOD FOR THE PREPARATION OF AMINOPHT-HALIDYLALKANE SALTS Glenn E; Ullyot, Philadelphia, Pa., assignor to Smith, Kline & French Laboratories, Philadelphia, Pa.,'a corporation of Pennsylvania No'Drawing. Original appl cation February 2, I 1946, Serial No. 645,228. Divided and this application August 26, 1948,, Serial No. 46,358

8 Claims. (01. 260'344.6)

This invention relates to a method for the preparation of aminophthalidylalkane salts and, moreparticularly, for the preparation of aminophthalidylalkane salts having the following structurez;

in which is H when R is a member of the group consisting of H, CH3, C2H5, Cal-I7, C4H9,

CH11 (anarylgroup; and R is CH3 when R is CH3; and, X is an acid radical.

I As illustrative of compounds within the above formula, which may be readily and efficiently prepared in high yield by the method according to this invention, may be mentioned by way of example aminophthalidylmethane hydrochloride, I-amino-l-phthalidylethane hydrochloride, ;1--

amino-lephthalidylpropane hydrochloride, 2- amino-2-phthalidylpropane hydrochloride, 1- amino-l-phthalidylbutane hydrochloride, v1 amino-l-phthalidylpentane hydrochloride, 1-

amino-l-phthalidylhexane hydrochloride, and .thenlike salts of other acids.

' -.Generally speaking, .the method according to this invention will comprise the reduction of a corresponding nitro Dhthalidylalkane having the following formula, under particular conditions:

NO: inwhich R is H where R is a member of the group consisting of H, CH3, C2H5, CaH1, C4H9, C5H11, an aryl group; and R is CH3 when R' is Nitrophthalidylalkanes having the structure of the above formula may be prepared by condensing phthalaldehydic acid with a nitroalkane CsHn, an aryl group;

2 and R is CH3 when R is CH -in an alkaline medium, as, for example, a sodium hydroxide solution in a known manner. According to the method of this invention, a nitrophthalidylalkane having the structure ofthe above formula is reduced under an initial hydrogenpressure of preferably not less than about 25 pounds in the presence of a noble metal catalyst and an acid having an ionization constant of 1.8 l0 or greater in a solvent for the nitrophthalidylalkane and the acid, and, preferably, also for the reduction product at reactiontemperature, at a temperature at which the reaction will proceed with reasonable rapidity and preferably such that undesirable side reactions will be avoided.

,When the eraction is completed, the product will be recovered by filtering hot to remove the catalyst, distilling off the solvent in vacuo, washing the residue, for example, with acetone, and purifying by crystallization from a solvent.

More specifically, the noble metal catalyst for use in carrying out the method may be, for example, palladium, platinum, or the like, and the catalyst will desirably be disposed in or on a carrier such as charcoal, finely divided carbon, kieselguhr, or the like.

The acid having an ionization constant of 1.8 10 or greater may be, for example, hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, or the like; and the solvent, for example, may be a lower monohydric alcohol, as, for example, ethyl alcohol, the methyl ether of ethylene glycol, or the like, or in the case of an organic acid, the acid itself may act as the solvent.

The initial hydrogen pressure will be at least 25 pounds and may be 100 pounds or more, desirably an initial hydrogen pressure of -500' pounds will be used.

The reaction will be carried out at a temperature, as has been indicated, which will cause the reaction to proceed I with reasonable rapidity without'causing undesirable side reactions. For

example, the temperature will desirably be within about the range 50 C.-100 C., and preferably within about the narrower range C.-80 0., or specifically about C.

I n proceeding with a strong mineral acid, at leastone equivalent of a strong mineral acid will be used per mol of nitrophthalidylalkane, as, for example, in the case of hydrochloric acid 45 cc. of 36% HCl to l00 gms. of nitrophthalidylalkane, with which about 400-500 cc. of solvent, as ethyl alcohol, will be used. I Generally speaking, the reaction will be comof heating.

3 plete in from about 4-8 hours and completion will be indicated when the hydrogen pressure ceases to drop.

The following examples will be morespecifi cally illustrativeof the method according to this invention:

Example 1 For the prepartion of 2-amifio- 2=phthalidyl v propane hydrochloride, eleven grams (0.05 in.) 2'- nitro-2-phthalidylpropane were dissolved in. 2Q0 cc. alcohol. One gram of carbon. met. 16% palladium chloride and 4.2 cc. of concentrated hydrochloric acid were added and the total was placed in a citrate bottle provided with aheatiiig -removed,ithe solid residue was washed with acetoneand collected. Ten and four-tenths grams or" hydrochloride salt were obtained.

Purification: The fractional crystallization of 1 amino 1 phthalidylpropane hydrochloride from 90% isopropyl alcohol resulted in the isolation of two racemic forms,., one of which melted :w'ith decomposition in the rarlg or ate-270 c.

and the other, which melted with decomposition in the range of 238-24012 C.

Recrystallization from alcohol gave a colorless crystalline product which decomposed at about 285+289 0. (closed capillary). This decomposition temperature varied somewhat with the rate 7 Example 2 For the production of l-amino-l-phthalidyl- V propanehydrochloridaone hundred grams (0.45

m.) of lenitro-l-phthaiidylpropane, 425 cc. of a mixture of 10% methyl alcohol and 90% ethyl alcohol 43 cc. (0.5 m.) concentrated hydrochloric acid, 100 cc. 16% palladium chloride solution and 10 g. activated carbon were placed in a suitable glass-lined autoclave and reduction was carried out at a temperature of 70 C. at an initial gauge pressure or 500 lbs/sq. in. while agitating the autociave. Reduction was completed in 5 to .7 hours when the gauge pressure dropped to 175- .200 lbs/sq. in. at room temperature. With the apparatus used the gauge pressure at room temperature should have been about 181 lbs/sq. in.

After reduction was completed, the cont'ents of the autoclave were removed, heated to nearthe boiling point and the catalyst wasrernoved 'by filtration. The solvent was removed by distillation and the product was washed with acetone.

The yield of crude product varied from 80-7-9596 andvmelted atfabout 208-223 C. with decomposi t on,

:campie 3 1'1 g. (0.05m) of l-nitro-l-phthalidylpropane' was dissolved in cc. (1.00 in.) of glacial acetic acid and 5 g. of 10% palladium-charcoal catalyst. The 11 g. wererdisso-lved and placed. in a citrate bottle and 5 g. of the catalyst were added.

Reduction was carried out on a Burgess-Parr apparatus at an initial gauge pressure of 50 pounds per square inch. The hydrogen uptake amounted to 0.14 mol. After removal of the catalyst by filtration, hydrochloric acid in excess of 0.05 equivalents was added to the filtrate and the sollvent removed in vacuo. The residue was washed with actone. 7.4 g. of crude 1-amino 1-phthalidylpropane hydrochloride were o bt ai ied, or a ,50-500 pounds.

' where X is an acid radical, which comprises reducin in the presence of a noble metal catalyst, a corresponding nitrophtlralidylalkane with hydrogen under pressure inthe presence of at least one molar equivalent of an acid selected from the group consisting of a mineral acid and. an organic acid having an ionization constant not less than 2. The method of producing aminophthalidylalkane salts according to claim 1; characterized bythe fact that the nitrophth'alidylalkane and the acid are in solution in a common solvent.

3. The method of producing aminop'hthalidyl' alkane salts according to claim 1, characterized by the fact that the nitrophthalidylalkane and the acid are in solution in a common solvent which is a solvent for the aminophthalidylalkane salt product of the reduction.

4. The method of producing aminophthalidylalkane salts according to claim 1,- characterized by the feet that the'reduction with h drogen under pressure is in the presence of an organic acid having an ionization constant not less than 1.8 10+ Y 5. The method of producing aminophtnandyl alkan' salts according to mini 1, characterized by the fact that the reduction is carried out under an initial hydrogen pressure of not less than about one atmosphere.

6. The method of producing aminophthalidylalkane salts aoording to claim 1, characterized by the fact that the reduction is carried out under a hydrogen pressure within the range 7. The method of producing-aminophthalidylalkane salts according to claim 1, characterized by the fact that the reduction is carried out under a hydrogen pressure or not less-than about 507-500 pounds andat a temperature of not less than about 50 C.

8. The method of producing ami'nophthalidyl: alkane salts. according to claim 1. characterized by thefact that palladium comprises the, catalys't, hydrochloric acid comprises the acid, initial hydrogen pressure within about, the range. 2 -5 pounds and the temperature-is within about the a range C.- C.

GLENN E. ULLYOT.

d fens e j 5 6 REFERENCES CITED Number Name Date The following references are of record in the 2'480'105 Uuyot 1949 file of this patent: OTHER REFERENCES UNITED STATES PATENTS 5 Szeki: Chemical Abstracts, v01. 31, 1937 page Number Name Dat 6644' m 22,264 Loewe Fm {1943 Ullyot et 9.1.: J. Organic Chemistry, v01. 10, No.

2,130,480 Austin Sept. 20, 1938 5, September 1945,1113429440- 

1. THE METHOD OF PRODUCING AMINOPHTHALIDYLALKANE SALTS HAVING THE FOLLOWING FORMULA: 